1. Field
The present invention is concerned with a novel process for the preparation of heterocyclic indene analogs, especially with the preparation of 4-hydroxycarbazole or N-protected 4-hydroxycarbazole. These compounds may be used as a building block for pharmaceutically active compounds, e.g. 1-(9H-carbazol-4-yloxy)-3-[[2-(2methoxy-phenoxy)ethyl]amino]-2-propanol (carvedilol). This compound is known in the art and is described for example in EP 0 004920. It is especially useful for prophylaxis and treatment of heart- and circulatory diseases like, for example, hypertension, coronary heart failure, angina pectoris and the like.
2. Description
Processes for the catalytic cyclocarbonylation of pyrrole and indole derivatives have been described by Hiday et al., Advances in Metal-Organic Chemistry, Volume 4, 275-309. These processes are characterized by high temperatures, high catalyst loadings and modest selectivity. Moreover, the educts necessary for the reactions in these processes are expensive, since they have to be prepared by lengthy procedures, and are not available commercially.
Surprisingly, it has been found that using the process according to the present invention, heterocyclic indene analogs, e.g. indole or carbazole derivatives (such as 4-hydroxycarbazole and N-protected 4-hydroxycarbazole) can be prepared from commercial educts and without the aforementioned disadvantages.
The subject invention provides a process preparing a compound of the formula: 
wherein
R1 and R2 are independently selected from the group consisting of hydrogen and lower-alkyl; or
R1 and R2 together with the ring carbon atoms to which they are attached form a monovalent carbocyclic or a monovalent carbocyclic aromatic ring or a monovalent carbocyclic or monovalent carbocyclic aromatic ring may substituted by halogen, lower-alkyl or lower-alkoxy;
X is O, S or Nxe2x80x94Z;
Z is an amino protecting group selected from the group consisting of SO2Ra, NMe2, CO2Rb and CON(Rc)2;
Ra is lower-alkyl or aryl; and
Rb and Rc are lower-alkyl.
This process comprises:
cyclocarbonylating a compound of formula: 
xe2x80x83wherein R3 is lower-alkyl, aryl or aralkyl, and R1, R2 and X are as defined above;
to form a compound of formula: 
xe2x80x83wherein R4 is lower-alkyl or aryl and R1, R2 and X are as defined above; and
saponifying the compound of formula (III) to produce the compound of formula (I).
It is favored where X is Nxe2x80x94Z or Z is SO2Ra and Ra is phenyl. It is also favored where R1 and R2 together with the ring carbon atoms to which they are attached form a phenyl ring. Another favored embodiment is where R3 is methyl or phenyl.
Beneficially, the cyclocarbonylating is carried out in the presence of a base, an anhydride, and a catalyst comprising a transition metal compound and a ligand. Preferred transition metal compounds are palladium salts, such as Pd(OAc)2, Pd2dba3, PdCl2, Pd2Cl2(xcfx80-allyl)2, PdCl2(NCMe)2, [Pd(NCMe)4](BF4)2 or Pd/C. Pd(OAc)2 is favored.
The ligand can be P(R5)(R6)(R7) or (R5)(R6)Pxe2x80x94(Y)xe2x80x94P(R5)(R6) wherein R5, R6 and R7 each independently are C1-8-alkyl, cyclohexyl, benzyl, naphthyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2- or 3- or 4-pyridyl, phenyl or phenyl which is substituted by C1-4-alkyl, C1-4-alkoxy, halogen, trifluoromethyl, lower alkylydenedioxy or phenyl and Y is binaphthyl, 6,6xe2x80x2-dimethyl- or 6,6xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl, or one of the groupsxe2x80x94(CH2)nxe2x80x94, xe2x80x94CH2CH2xe2x80x94P(C6H5)xe2x80x94CH2CH2xe2x80x94, 
and n is a number of 1-8. A preferred ligand is selected from the group consisting of triphenylphosphine, and 
More favored is triphenylphosphine, 
The cyclocarbonylating can be carried out in the presence of a base selected from the group consisting of tri-alkyl-amines, di-alkyl-aryl-amines, pyridines, alkyl-N-piperidines, sodium hydroxide, potassium hydroxide or salts of carbonic acids. Presently, triethylamine is favored.
Anhydrides such as (R4(Cxe2x95x90O))2O, wherein R4 is as defined above are preferred. Favored anhydrides include acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, pivalic anhydride, and benzoic anhydride.
Saponifying is can be performed in a biphasic mixture of sodium hydroxide in toluene or in a homogeneous mixture of sodium methylate in methanol.
A more favored process is where the cyclocarbonylating is carried out in the presence of a base selected from the group consisting of tri-alkyl-amines, di-alkyl-aryl-amines, pyridines, alkyl-N-piperidines, sodium hydroxide, potassium hydroxide and salts of carbonic acids. An anhydride of the formula (R4(Cxe2x95x90O))2O, wherein R4 is as defined as above is used. In addition, a catalyst comprising a transition metal compound and a ligand is provided. The transition metal compound is selected from the group consisting of Pd(OAc)2, Pd2dba3, PdCl2, Pd2Cl2(xcfx80-allyl)2, PdCl2(NCMe)2, [Pd(NCMe)4](BF4)2, and Pd/C. The ligand is selected from the group consisting of P(R5)(R6)(R7) and (R5)(R6)Pxe2x80x94(Y)xe2x80x94P(R5)(R6) wherein R5, R6 and R7 each independently are C1-8-alkyl, cyclohexyl, benzyl, naphthyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2- or 3- or 4-pyridyl, phenyl or phenyl which is substituted by C1-4-alkyl, C1-4-alkoxy, halogen, trifluoromethyl, lower alkylydenedioxy or phenyl and Y is binaphthyl, 6,6xe2x80x2-dimethyl- or 6,6xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl, or one of the groups xe2x80x94(CH2)nxe2x80x94, xe2x80x94CH2CH2xe2x80x94P(C6H5)xe2x80x94CH2CH2xe2x80x94, 
and n is a number of 1-8.
All combinations of the above bases, anhydrides, and catalysts are envisioned, as are the choices of ligands, transition metal compounds and saponifying agents.
The subject invention also provides a compound of formula: 
wherein R8 is hydrogen, acetyl or benzoyl.